TRINTELLIX® (vortioxetine) Prescribing Information Now Includes New Data Showing Improvement in Processing Speed, an Important Aspect of Cognitive Function in Acute Major Depressive Disorder (MDD)

May 2, 2018

First antidepressant with U.S. labelling approved with Digit Symbol Substitution Test (DSST) data recognized as a clinically meaningful measure in acute MDD

Osaka, Japan and Deerfield, Ill. (May 2, 2018) – Takeda Pharmaceutical Company Limited (Takeda; TSE: 4502) and H. Lundbeck A/S (Lundbeck; LUN.CO, LUN DC, HLUYY) today announced the U.S. Food and Drug Administration (FDA) approved a supplemental new drug application for TRINTELLIX® (vortioxetine). TRINTELLIX is the first FDA-approved treatment for MDD where the U.S. labelling now includes data from the largest replicated clinical studies on an important aspect of cognitive function in acute major depressive disorder (MDD, depression). The FOCUS and CONNECT studies showed TRINTELLIX had a positive effect on processing speed, an important aspect of cognitive function that may be impaired in adult patients with acute MDD.

FOCUS and CONNECT, two eight-week, randomized, double-blind, placebo-controlled studies, were conducted to evaluate the effect of TRINTELLIX on the Digit Symbol Substitution Test (DSST) during the treatment of acute MDD. The DSST is a neuropsychological test that most specifically measures processing speed, an aspect of cognitive function that may be impaired in MDD. The effects observed on DSST may reflect improvement in depression. Comparative studies have not been conducted to demonstrate a therapeutic advantage over other antidepressants on the DSST.

“Many of my MDD patients recognize the mood and physical attributes of depression, but do not often recognize that their cognitive symptoms may also be part of their depression. As part of a comprehensive treatment approach, it’s important for clinicians to talk to patients about all symptoms associated with depression. This updated TRINTELLIX labelling regarding improvement in processing speed provides important information to improve discussions between healthcare providers and patients about their depression,” said Dr. Gregory Mattingly, Associate Clinical Professor, Department of Psychiatry, Washington University School of Medicine.

Depression is a complex disorder that is more than just sadness. This condition has a wide range of symptoms, including depressed mood or loss of interest, physical symptoms such as sleep problems, decrease or increase in appetite, significant weight loss when not dieting or weight gain, and cognitive symptoms, like difficulty concentrating or slowed thinking. The prevalence of cognitive impairment associated with MDD is high.

“With my depression, I felt like my thoughts slowed down. It was as if my brain just couldn’t keep up. After speaking with my doctor, I was surprised to learn that this could be part of my depression,” said David, a patient who spoke about his experience with depression at a FDA Advisory Committee Meeting in 2016.

“Years of research, including the FOCUS and CONNECT studies, have helped us better understand how complex and debilitating depression can be for people and reinforces how important innovation is in bringing potential options to those suffering from depression,” said Anders Gersel Pedersen, Executive Vice President, Head of Drug Development, Lundbeck.

“We are pleased with the FDA’s approval of our sNDA to include data on an important aspect of cognitive function in MDD in the U.S. labelling of TRINTELLIX. The FOCUS and CONNECT data provides additional clinical information to healthcare professionals for people suffering from depression,” said Emiliangelo Ratti, Senior Vice President, Head of Neuroscience Therapeutic Area Unit, Takeda.

The FDA approved TRINTELLIX on September 30, 2013 for the treatment of MDD in adults. Vortioxetine is furthermore approved in 77 countries (including Europe, Canada, Chile, China, Mexico, Argentina, South Korea, Turkey, Australia, Hong Kong, Singapore and South Africa). It is available in more than 60 countries to date.

About Major Depressive Disorder (MDD)

MDD is a complex mental health illness that affects approximately 14 million people annually. Also known as clinical depression, MDD is the leading cause of disability worldwide and a major contributor to the overall global burden of disease.MDD may trigger emotional, cognitive and physical symptoms, which includes depressed mood, loss of interest or pleasure, significant weight loss or gain or change in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, diminished ability to think or concentrate, or indecisiveness, and recurrent suicidal ideation.

About TRINTELLIX (vortioxetine)

The mechanism of the antidepressant effect of TRINTELLIX is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors. The contribution of each of these activities to TRINTELLIX’s antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity. The clinical relevance of this is unknown.

TRINTELLIX was discovered by Lundbeck researchers in Copenhagen, Denmark. The clinical trial program in the U.S. was conducted jointly by Lundbeck and Takeda, and Takeda holds the new drug application for the U.S. market. TRINTELLIX is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals U.S.A., Inc. For more information, visit www.Trintellix.com.

The World Health Organization has issued an Anatomical Therapeutic Chemical (ATC) code for TRINTELLIX that places it in the category of “Other” antidepressants.

The most commonly observed adverse events in MDD patients treated with TRINTELLIX in 6-8 week placebo-controlled studies (incidence greater than or equal to 5 percent and at least twice the rate of placebo) were nausea, constipation and vomiting. Overall, 5 to 8 percent of the patients who received TRINTELLIX 5 to 20 mg/day in short-term trials discontinued treatment due to an adverse reaction, the most common being nausea, compared with 4 percent of placebo-treated patients in these studies. TRINTELLIX and other antidepressants may cause serious side effects. See Important Safety Information below.

In clinical studies, TRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in 6-8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to TRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between TRINTELLIX and placebo-treated patients. Some reports of weight gain have been received since product approval. TRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

The recommended starting dose of TRINTELLIX is 10 mg once daily without regard to meals. The dose should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the U.S. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses. The available doses provide important flexibility for physicians to help address the variability of patient needs.

TRINTELLIX is available as 5 mg, 10 mg and 20 mg tablets.

IMPORTANT SAFETY INFORMATION

Suicidal Thoughts and Actions and Antidepressant Drugs

Antidepressants may increase suicidal thoughts or actions in some children, teens or young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. People who have (or have a family history of) bipolar illness, or suicidal thoughts or actions may have a particularly high risk. Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings. Call your healthcare provider right away if symptoms such as anxiety, irritability, impulsivity, trouble sleeping, aggressive behavior or suicidal thoughts are new, worse or worry you. TRINTELLIX has not been evaluated for use in patients under 18.

Do not take TRINTELLIX if you:

Are allergic to vortioxetine or any of the ingredients in TRINTELLIX

Take a Monoamine Oxidase Inhibitor (MAOI).Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid; do not take an MAOI within 21 days of stopping TRINTELLIX; do not start TRINTELLIX if you stopped taking an MAOI in the last 14 days

TRINTELLIX may cause serious side effects including:

Serotonin Syndrome: A potentially life-threatening problem that can happen when medicines such as TRINTELLIX are taken with certain other medicines. Symptoms may include agitation, hallucinations, coma or other changes in mental status; problems controlling movements or muscle twitching, stiffness or tightness; fast heartbeat, high or low blood pressure; sweating or fever; nausea, vomiting or diarrhea.

Abnormal bleeding or bruising: TRINTELLIX and other serotonergic antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAID), or aspirin.

Visual problems: May include eye pain, changes in vision, swelling or redness in or around the eye. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

Low salt (sodium) levels in the blood: Symptoms may include headache; difficulty concentrating, memory changes or confusion; weakness and unsteadiness on your feet; and in severe or sudden cases hallucinations, fainting, seizures or coma. If not treated, severe low sodium levels can cause death.

Before starting TRINTELLIX, tell your healthcare provider if you have or had liver problems, seizures or convulsions, bipolar disorder (manic depression) or mania, low salt (sodium) levels in your blood, bleeding problems, drink alcohol, have any other medical conditions or if you are pregnant, nursing, plan to become pregnant, or plan to nurse.

TRINTELLIX and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together. Tell your healthcare provider if you plan on or are taking any other prescription and non-prescription medicines, vitamins and herbal supplements including medicines for migraine headaches, such as triptans; medicines used to treat mood, anxiety, psychotic or thought disorders such as tricyclics, lithium, SSRIs, SNRIs, bupropion, buspirone or antipsychotics; MAOIs including linezolid (a specific antibiotic); over-the-counter supplements such as tryptophan or St. John's wort; and the following medicines: aspirin, NSAIDs, warfarin (Coumadin®, Jantoven®), diuretics, rifampin, carbamazepine, phenytoin, quinidine, tramadol or fentanyl.

Common side effects of TRINTELLIX include: nausea, constipation or vomiting. These are not all the possible side effects of TRINTELLIX.

Do not start or stop taking TRINTELLIX without talking to your healthcare provider first. Suddenly stopping TRINTELLIX when you take higher doses may cause you to have side effects including headache, stiff muscles, mood swings, sudden outbursts of anger, dizziness or feeling lightheaded, or runny nose.

Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries. For more information, visit https://www.takeda.com/newsroom/.

About Takeda Neuroscience

Neuroscience is a core therapeutic area for Takeda. Our mission is to provide innovative medicines for targeted patient populations suffering from neuropsychiatric disorders for whom there are no treatments available. We identify targets either genetically linked with specific neuropsychiatric disorders or with high association to the disease pathophysiology, design and operationalize clinical trials in novel ways in an effort to overcome historical challenges, and collaborate with patients, academic institutions, pharmaceutical and biotechnology partners, payors, regulators and prescribers to integrate their unique expertise and perspective. Takeda’s current global portfolio consists of five approved medicines to treat adults with: Major Depressive Disorder (MDD), Alzheimer’s-type dementia, insomnia, multiple sclerosis, and Parkinson's disease.In addition, there are many novel compounds in clinical development for targeted patient populations.

About H. Lundbeck A/S

H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) is a global pharmaceutical company specialized in psychiatric and neurological disorders. For more than 70 years, we have been at the forefront of research within neuroscience. Our key areas of focus are Alzheimer's disease, depression, Parkinson's disease and schizophrenia.

Our approximately 5,000 employees in 55 countries are engaged in the entire value chain throughout research, development, manufacturing, marketing and sales. Our pipeline consists of several late-stage development programs and our products are available in more than 100 countries. We have production facilities in Denmark, France and Italy. Lundbeck generated revenue of DKK 17.2 billion in 2017 (EUR 2.3 billion; USD 2.6 billion).

For additional information, visit www.lundbeck.com and connect on Twitter at @Lundbeck.

Lundbeck in the U.S.

In the U.S., Lundbeck employs more than 800 people focused solely on accelerating therapies for brain disorders. With a special commitment to the lives of patients, families and caregivers, Lundbeck U.S. actively engages in hundreds of initiatives each year that support our patient communities.

For additional information, visit www.lundbeckus.com and connect on Twitter at @LundbeckUS.